Angiogenesis, the process by which new blood vessels develop from existing vasculature, is a critical step in the progression of solid tumors. In response to growth factors, a subset of endothelial cells is activated and migrate away from their parent vessels. Though many factors such as VEGF and FGF have been implicated in promoting the migration of endothelial cells, little is known about what molecules regulate and coordinate the migratory machinery in this cohort of highly motile cells.
Development of a vascular system is a fundamental requirement for many physiological and pathological processes. Active growth of embryos and tumors requires an adequate blood supply. Pro-angiogenic factors promote new blood vessel formation and maintenance via a process generally referred to as angiogenesis. Vascular formation is a complex but orderly biological event involving all or many of the following steps: a) Endothelial cells (ECs) within existing vessels proliferate, or new ECs form via differentiation from progenitor cells; b) Newly formed ECs migrate to target sites and coalesce to form cord-like structures; c) vascular cords then undergo tubulogenesis to form vessels with a central lumen d) existing cords or vessels send out sprouts to form secondary vessels; e) primitive vascular plexus undergo further remodeling and reshaping; and f) peri-endothelial cells are recruited to encase the endothelial tubes, providing maintenance and modulatory functions to the vessels; such cells including pericytes for small capillaries, smooth muscle cells for larger vessels, and myocardial cells in the heart. Hanahan, D. Science 277:48-50 (1997); Hogan, B. L. & Kolodziej, P. A. Nature Reviews Genetics. 3:513-23 (2002); Lubarsky, B. & Krasnow, M. A. Cell. 112:19-28 (2003).
Angiogenesis is implicated in the pathogenesis of a variety of disorders. These include malignant tumor growth, atherosclerosis, retrolental fibroplasia, hemangiomas, chronic inflammation, intraocular neovascular diseases such as proliferative retinopathies, e.g., diabetic retinopathy, age-related neovascular macular degeneration (nvAMD), neovascular glaucoma, immune rejection of transplanted corneal tissue and other tissues, rheumatoid arthritis, and psoriasis. Folkman et al., J. Biol. Chem., 267:10931-10934 (1992); Klagsbrun et al., Annu. Rev. Physiol. 53:217-239 (1991); and Garner A., “Vascular diseases”, in: Pathobiology of Ocular Disease. A Dynamic Approach, Garner A., Klintworth G K, eds., 2nd Edition (Marcel Dekker, NY, 1994), pp 1625-1710.
In the case of tumor growth, angiogenesis appears to be crucial for the transition from hyperplasia to neoplasia, and for providing nourishment for the growth and metastasis of the tumor. Folkman et al., Nature 339:58 (1989). The neovascularization allows the tumor cells to acquire a growth advantage and proliferative autonomy compared to the normal cells. A tumor usually begins as a single aberrant cell, which can proliferate only to a size of a few cubic millimeters due to the distance from available capillary beds, and it can stay ‘dormant’ without further growth and dissemination for a long period of time. Some tumor cells then switch to the angiogenic phenotype to activate endothelial cells, which proliferate and mature into new capillary blood vessels. These newly formed blood vessels not only allow for continued growth of the primary tumor, but also for the dissemination and recolonization of metastatic tumor cells. Accordingly, a correlation has been observed between density of microvessels in tumor sections and patient survival in breast cancer as well as in several other tumors. Weidner et al., N. Engl. J. Med 324:1-6 (1991); Horak et al., Lancet 340:1120-1124 (1992); Macchiarini et al., Lancet 340:145-146 (1992). The precise mechanisms that control the angiogenic switch is not well understood, but it is believed that neovascularization of tumor mass results from the net balance of a multitude of angiogenesis stimulators and inhibitors (Folkman, 1995, Nat Med 1(1):27-31). MAP4K4 may play a role in promoting tumor cell migration/invasion. MAP4K4 RNAi inhibited both migration and invasion of SKOV3 human ovarian cancer cells in vitro (Collins et al, 2006, PNAS 103:3775-3780). Analysis of human tumors, including pancreatic, hepatocellular and colorectal cancer, shows a link between high MAP4K4 expression and worse prognosis, with increased tumor size and increased metastasis (Liang et al, 2008, Clin Cancer Res 14:7043-7049, Liu et al, 2011, Clin Cancer Res 17:710-720, Hao et al, 2010, J Pathol 220:475-489).